Targeting Mitochondrial Dysfunction in Neurodegenerative Disease

It’s long been known that the brain is an energy
glutton: Most estimates suggest that it requires
about 20 percent of the body’s total energy stores to work effectively. That
energy is produced by mitochondria, specialized rod-shaped organelles in every
cell in the body. So perhaps it is no surprise that problems with mitochondrial
function in neurons have been linked to a host of progressive neurodegenerative
disorders—one of which is Friedreich’s ataxia, a rare but devastating disease
that progressively kills off nerve cells in the brain and spinal cord. Now,
scientists at the University of California, Davis have identified how frataxin,
the gene that causes Friedreich’s ataxia, affects mitochondrial function. That
understanding may lead to new, more effective potential treatments for Friedreich’s
ataxia as well as other forms of neurodegenerative disease.

Tiny powerhouses,
large consequences

Open any middle school science book and you’ll see
mitochondria described as “cellular powerhouses.” And rightly so: These small organelles are responsible for
producing adenosine triphosphate (ATP), the molecule that supplies energy to
the cell and, consequently, to the brain and the body.

“You can think of mitochondria
as factories that produce energy in cells,” says Tetsuo Ashizawa, a neurologist
who studies the mitochondrial dysfunction of neurodegenerative diseases at
Houston Methodist Hospital. “They are particularly important for cells which
have higher energy demands. The brain is one of the highest energy-demanding
tissues in the body, constantly generating electricity across the organ so
neurons can communicate with one another across the organ. So when mitochondria
are corrupted, neurons are particularly susceptible to damage.”

Mitochondrial dysfunction can result in neurodegeneration
in additional ways, as well, says Giovanni Manfredi, a researcher at the Brain
and Mind Research Institute at the Weill Cornell School of Medicine.

“Neural degeneration can be caused by primary
mitochondrial defects like you find in genetic diseases that affect
mitochondrial proteins or enzymes. And the primary issue there is largely due
to the inability of mitochondria to produce enough energy,” he says. “But
mitochondria also do a lot of other important things beyond making energy. They
mediate cell metabolism—making amino acids, destroying amino acids, making the
substance to make nucleotides. They help buffer calcium, which is an important
cellular messenger. They can promote apoptosis, or programmed cell death. It’s
kind of paradoxical, because mitochondria are the provider of life for the
cells. But they can also act as the executioners of brain cells when they are
sick.”

Understanding the
“orphan” disease

In 1996, scientists discovered
that Friedreich’s ataxia, a rare genetic disorder that leads to progressive
damage to the brain and spinal cord, was the result of a specific mutation to the
frataxin (FXN) gene. Approximately
6,000 people in the US have the disease; there are currently no Food and Drug
Administration (FDA) approved treatments and most people diagnosed with it die
before they turn 40. Gino Cortopassi, a biochemist at the University of
California, Davis School of Veterinary Medicine, wanted to see if they could
identify possible drug treatments.

“It’s a
horrible, horrible disease,” says Cortopassi. “And it’s an ‘orphan’ disease,
with no reliable treatments—most mitochondrial diseases are—so we wanted to see
if we could find something that might help.”

While
scientists understood that the FXN gene mutation led to Friedreich’s ataxia,
they did not know how the reduction of a single protein led to its myriad
symptoms. Cortopassi and colleagues looked at the effects of FXN deficiency in
a mouse model of the disease, in blood collected from patients with the
disorder, and from fibroblast cell models. They found that the lack of frataxin
results in a significant decrease in mitochondrial levels.

Cortopassi and
colleagues then tried to restore the balance by repurposing FDA-approved drugs
that are currently used for a variety of other medical disorders. They found that
a drug called dimethyl fumarate (DMF), currently used to treat multiple
sclerosis, also increased frataxin—and the number of mitochondria—in cells treated with the drug. The results of both studies
were published in April 2017 in Human
Molecular Genetics.

“This is a drug
that induces mitochondrial number and function. And it’s possible that it could
be applicable beyond Friedreich’s ataxia,” says Cortopassi. “Multiple sclerosis
is another neurodegenerative disorder with a deficiency of mitochondria. And
when treated with this drug, we saw an increase in mitochondrial number and
gene expression in the white blood cells of MS patients, too.”

What’s next?

Cortopassi
hopes to take DMF to clinical trial for Friedreich’s ataxia patients soon. He
also thinks measuring mitochondrial number could be an important biomarker to
test the efficacy of treatments for other neurodegenerative disorders as well.
Manfredi agrees.

With a simple blood draw, one could count how many mitochondria
are in the platelets. “Because platelets are generated from mitochondrial sets
in the bone marrow, once the cells are exposed to the drug, you should see more
mitochondria—which would be an easy biomarker to see if the drug is working.”

But Cortopassi’s main goal is to find
effective treatments for these mitochondrial diseases. He believes finding ways
to increase mitochondria could also help people with other neurodegenerative
and muscle disorders that show mitochondrial dysfunction. Ashizawa says it is a promising approach, but
clinicians need to be mindful that in more complex disorders like Alzheimer’s
and Parkinson’s disease, mitochondrial dysfunction generally occurs after the
initial neuronal damage has already begun.

“Unless we can
shut down the root cause of these disorders, increasing the number of mitochondria
can only be a palliative treatment at best,” he says. “But for diseases like
Friedrich’s ataxia, where the problem is directly linked to mitochondria, this
kind of approach has a great deal of promise.”